Summary: The long-term goal of this proposal is to develop novel therapeutics for a serious unmet medical need, namely acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) for which there are no treatments other than supportive care. The mechanisms of kidney injury and its progression to CKD are largely unknown and this proposal aims to fill some of these knowledge gaps. The short-term goal of this proposal is to validate a novel target for treating AKI and its progression to CKD for future drug development. This target is neutral ceramidase (NCD), an enzyme involved in metabolism of the sphingolipid ceramide. The proposal is based on a strong foundation of supporting preliminary data that indicates that mice lacking NCD are protected in models of AKI and CKD and in vitro data indicating that deletion or inhibition of NCD increases autophagy and protects cells from a variety of cellular stresses. Thus, this proposal will test the hypothesis that deletion or inhibition of NCD confers protection from AKI and injury-induced CKD via upregulation of autophagy. We will test this hypothesis with three interrelated but independent specific aims that will (1) determine the mechanism of protection of kidney cells in vitro from cellular stress when NCD is deleted or inhibited; (2) determine the role of NCD in AKI; and (3) determine the role of NCD in kidney injury progression to CKD. Data obtained in this proposal will provide many scientific and translational advances that are essential for achieving our long-term goal of developing therapeutics for this unmet medical need.